TGF-β and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies

被引：112

作者：

Courau, Tristan ^{[1
,2
]}

Nehar-Belaid, Djamel ^{[1
,2
]}

Florez, Laura ^{[1
,2
]}

Levacher, Beatrice ^{[1
,2
]}

Vazquez, Thomas ^{[1
,2
]}

Brimaud, Faustine ^{[1
,2
,3
]}

Bellier, Bertrand ^{[1
,2
]}

Klatzmann, David ^{[1
,2
,3
]}

机构：

[1] Sorbonne Univ, UPMC Univ Paris, Paris, France

[2] INSERM UMR S 959, Paris, France

[3] Grp Hosp Pitie Salpetriere, AP HP, Dept Biotherapies, Clin Invest Ctr Biotherapy & Inflamat Immunopatho, F-75013 Paris, France

来源：

JCI INSIGHT | 2016年 / 1卷 / 09期

基金：

欧洲研究理事会;

关键词：

REGULATORY T-CELLS; ENDOTHELIAL GROWTH-FACTOR; DENDRITIC CELLS; IMMUNE CELLS; ANTITUMOR; BLOCKADE; EXPRESSION; MATURATION; MICROENVIRONMENT; COMBINATION;

D O I：

10.1172/jci.insight.85974

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Tregs imprint an early immunotolerant tumor environment that prevents effective antitumor immune responses. Using transcriptomics of tumor tissues, we identified early upregulation of VEGF and TGF-beta pathways compatible with tolerance imprinting. Silencing of VEGF or TGF-beta in tumor cells induced early and pleiotropic modulation of immune-related transcriptome signatures in tumor tissues. These were surprisingly similar for both silenced tumors and related to common downstream effects on Tregs. Silencing of VEGF or TGF-beta resulted in dramatically delayed tumor growth, associated with decreased Tregs and myeloid-derived suppressor cells and increased effector T cell activation in tumor infiltrates. Strikingly, co-silencing of TGF-beta and VEGF led to a substantial spontaneous tumor eradication rate and the combination of their respective inhibitory drugs was synergistic. VEGF and/or TGF-beta silencing also restored tumor sensitivity to tumor-specific cell therapies and markedly improved the efficacy of anti-PD-1/anti-CTLA-4 treatment. Thus, TGF-beta and VEGF cooperatively control the tolerant environment of tumors and are targets for improved cancer immunotherapies.

引用

页数：16

共 58 条

[1] Natural and induced T regulatory cells in cancer [J].

Adeegbe, Dennis O. ;

Nishikawa, Hiroyoshi .

FRONTIERS IN IMMUNOLOGY, 2013, 4

[2]

[Anonymous], 2015, MATH PROB ENG, DOI DOI 10.1016/J.CMET.2015.09.010

[3]

Ashburner M, 2001, GENOME RES, V11, P1425, DOI 10.1101/gr.180801

[4] Antigen quality determines the efficiency of antitumor immune responses generated in the absence of regulatory T cells [J].

Bergot, A-S ;

Durgeau, A. ;

Levacher, B. ;

Colombo, B. M. ;

Cohen, J. L. ;

Klatzmann, D. .

CANCER GENE THERAPY, 2010, 17 (09) :645-654

[5] Transforming growth factor-β1 sustains the survival of Foxp3+ regulatory cells during late phase of oropharyngeal candidiasis infection [J].

Bhaskaran, N. ;

Quigley, C. ;

Weinberg, A. ;

Huang, A. ;

Popkin, D. ;

Pandiyan, P. .

MUCOSAL IMMUNOLOGY, 2016, 9 (04) :1015-1026

[6] TGFβ:: the molecular Jekyll and Hyde of cancer [J].

Bierie, Brian ;

Moses, Harold L. .

NATURE REVIEWS CANCER, 2006, 6 (07) :506-520

[7] Regulatory and effector T cell activation levels are prime determinants of in vivo immune regulation [J].

Billiard, Fabienne ;

Litvinova, Elena ;

Saadoun, David ;

Djelti, Fathia ;

Klatzmann, David ;

Cohen, Jose L. ;

Marodon, Gilles ;

Salomon, Benoit L. .

JOURNAL OF IMMUNOLOGY, 2006, 177 (04) :2167-2174

[8] Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression [J].

Chang, Chih-Hao ;

Qiu, Jing ;

O'Sullivan, David ;

Buck, Michael D. ;

Noguchi, Takuro ;

Curtis, Jonathan D. ;

Chen, Qiongyu ;

Gindin, Mariel ;

Gubin, Matthew M. ;

van der Windt, Gerritje J. W. ;

Tonc, Elena ;

Schreiber, Robert D. ;

Pearce, Edward J. ;

Pearce, Erika L. .

CELL, 2015, 162 (06) :1229-1241

[9] Regulatory T cells prevent CD8 T cell maturation by inhibiting CD4 th cells at tumor sites [J].

Chaput, Nathalie ;

Darrasse-Jeze, Guillaume ;

Bergot, Anne-Sophie ;

Cordier, Corinne ;

Ngo-Abdalla, Stacie ;

Klatzmann, David ;

Azogui, Orly .

JOURNAL OF IMMUNOLOGY, 2007, 179 (08) :4969-4978

[10] Hypoxia promotes tumor growth in linking angiogenesis to immune escape [J].

Chouaib, Salem ;

Messai, Yosra ;

Couve, Sophie ;

Escudier, Bernard ;

Hasmim, Meriem ;

Noman, Muhammad Zaeem .

FRONTIERS IN IMMUNOLOGY, 2012, 3

← 1 2 3 4 5 6 →